CH644597A5 - IMIDAZOLE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM. - Google Patents

Description

The invention relates to imidazole derivatives and, in particular, to certain N- (phenoxyalkyl) imidazoles, which are substituted in the phenyl ring by acidic and polar groups.

Such compounds are able to inhibit the action of the thromboxane synthetase enzyme without significantly inhibiting the action of the prostacyclin synthetase or cyclo-oxygenase enzymes. The compounds according to the invention can therefore be used, for example, in the treatment of thrombosis, ischemic heart diseases, 25 strokes, transient ischemic attacks, migraines and in the case of vascular complications from diabetes.

According to the invention, imidazole derivatives of the following general formula are provided:

N

N-

(cv "-

wherein shark means chlorine, bromine or iodine, is implemented.

in which mean:

R = N02, CN, S02NH2, Cj-Cj-alkanoyl, C02R2, CH2C02-R2, 0CH2C02R2, CONHR3, CH2CONHR3, OCH2-40 CONHR3, CON (R4) 2, CH2CON (R4) 2, OCH2CON (R4) 2, , CH2NHR5, tetrazolyl, CH2-tetrazolyl and OCH2-tetrazolyl;

R1 = H, Cj-Qj-alkyl, Cx-C4-alkoxy or halogen; R2 = H or CrC4 alkyl;

45 R3 = H, CrC4-AlkyI, CrC4-alkanoyl, C1-C4-alkylsulfonyl, CN, benzoyl or benzenesulfonyl, the phenyl ring in these benzoyl or benzenesulfonyl groups optionally having one or more CrC4-alkyl, CrC4-alkoxy or CF3 radicals or halogen atoms is substituted;

each R4 = Cj-Q-alkyl or two R4 radicals together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino radical;

55 R5 = H, Cj-Q-alkanoyl, Cj-C4-alkoxycarbonyl, Carbamoyl, C1-C4-alkylcarbamoyl; and n = 2 or 3,

as well as the pharmaceutically acceptable acid addition salts thereof.

60

The invention is suitable for inhibiting the action of the thromboxane synthetase enzyme in an animal, and in humans without significant inhibiting action of the prostacyclin synthetase or cyclo-oxygenase enzymes, where an effective amount of an in animal or human A compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition or a medicament which contains such

3rd

644 597

Compound or a salt thereof, optionally with a pharmaceutically acceptable diluent and / or carrier, is applied.

One embodiment of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing such a compound or salt together with a pharmaceutically acceptable diluent or carrier for use in the treatment of a Animal or human to inhibit the action of the thromboxane synthetase enzyme without significantly inhibiting the action of the prostacyclin synthetase or cyclooxygenase enzyme.

The invention further relates to a medicament which contains a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.

Pharmaceutically acceptable acid addition salts of the compounds of the invention are salts with acids which contain pharmaceutically acceptable anions, e.g. the hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or acidic phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate and p-to lu olsulfonate salts.

In the description, “halogen” means fluorine, chlorine, bromine or iodine. Alkyl and alkoxy radicals with three or more carbon atoms can be straight-chain or branched-chain. Alkanoyl residues with 4 carbon atoms can be straight-chain or branched-chain.

Preferred compounds according to the invention are 'compounds in which n = 2, furthermore those in which the radical R1 is a hydrogen atom, and those compounds in which the radical R is a carboxy, carbamoyl or N- (mono- or Dimethyl) carbamoyl radical, in particular in the 4-position, and the radical R1 are a hydrogen atom. Particularly preferred individual compounds are: 1 - [2- (4-carbamoylphenoxy) ethyl] imidazole, l- [2- (4-N-methylcarbamoylphenoxy) ethyl] imidazole, l- [2- (4-N, N -DimethyIcarbamoyIphenoxy) -ethyl] -imidazole,

and

1 - [2- (4-carboxyphenoxy) ethyI] imidazole,

the latter connection being particularly preferred.

The compounds of the invention can be made in a number of different ways. In a procedure according to the invention, the compounds are prepared by reacting imidazole with an alkali metal hydride and a compound in which the radicals R and R1 have the meaning given above and "shark" means chlorine, bromine or iodine.

The reaction is conveniently carried out by adding 1 equivalent of the alkali metal hydride, e.g. sodium hydride to a solution of imidazole in a dry, inert, organic solvent, e.g. N, N-dimethylformamide, dimethyl sulfoxide or hexamethylphosphoramide. The solution is preferably cooled during the initial stages of the addition, but the reaction mixture is generally heated to 100 ° C for 10-15 minutes for the reaction to complete once the addition of the alkali metal hydride is complete. The solution is then cooled and the halide of formula (II) is added, preferably in an amount of 1 equivalent or a little excess in the form of a solution in the same solvent.

5 The completion of the reaction can be carried out at room temperature, but it is generally preferred to warm the reaction mixture, e.g. to 100 ° C to accelerate the reaction. Under these conditions, the reaction is usually essentially complete within 10 hours.

The reaction product is worked up in a conventional manner, e.g. by removing the solvent under vacuum, by solvent extraction and by recrystallization.

15 Certain radicals R can of course be obtained by chemical conversion reactions, and these possibilities are known per se to the person skilled in the art. For example, compounds of formula (I) in which R is an amino group can be conveniently prepared by reduction 20 of the corresponding compound of formula (I) in which R is nitro. This reduction can be carried out in a simple manner by catalytic hydrogenation over a metal catalyst, for example using Raney nickel, in an organic solvent which is inert to the reaction at room temperature or alternatively using iron powder in hydrochloric acid. A similar reduction of a compound of formula (I) wherein R is cyano-nor, e.g. using lithium aluminum 30 hydride provides the corresponding compound of formula (I) wherein R is an aminomethyl radical.

The amines thus produced can of course be converted to a variety of N-substituted derivatives by conventional reactions. Thus, compounds of the formula (I) in which the radical R is an amino or aminomethyl radical can be converted to compounds in which the radical R is one of the radicals NHR5 or CH2NHR5 and R5 is a formyl, C2-C4-alkanoyl -, Alkoxycarbonyl-, carbamoyl or alkylcarbamoyl residue, can be converted by reaction with a suitable formylating agent, acylating agent, alkyl chloroformate, potassium cyanate or an alkyl isocyanate.

For example, the reaction of the aminomethyl-substituted derivative with acetic anhydride in acetic acid gives the corresponding compound, in which the radical R = -CH2N'HCOCH3; a similar reaction of an amine derivative, in which the radical R = NH2, with potassium cyanate gives the corresponding ureide derivative or in which the radical R = -N'HCONHa.

so The hydrolysis of a compound of formula (I), wherein R is a cyano group, with alkaline hydrogen peroxide can be used to produce a carbamoyl derivative, where the group R = CONH2, or alternatively, a more vigorous hydrolysis of the nitrite or carbamoyl-55 - derivates the corresponding acid, wherein R is a carboxyl radical. Acids can also be obtained by conventional acid or base catalyzed hydrolysis of the corresponding esters, i.e. if R represents one of the following radicals: C02R2, CH2C02R2 or 0CH2C02R2, 60 in which R2 is a Cj-C4-alkyl radical, e.g. using aqueous sodium hydroxide solution or aqueous hydrochloric acid.

The acids can be converted to a variety of derivatives by conventional methods. Thus the formation of the acid chloride, e.g. by reaction with thio-65 nyl chloride, and the subsequent reaction with ammonia the amides, in which the radical R = CONH2. Similarly, the reaction of the acid chloride with a C1-C4 lower alkylamine gives compounds in which the rest

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4th

R = CONHR3, where R3 is a CrC.ralkyl radical, or reaction with a di-lower alkylamine or with pyrrolidine, piperidine or morpholine gives compounds in which the radical R = CON (R4) 2.

The amides in which the radical R = CONH2, CH2CONH2 or OCH2CONH2 can also be obtained from the corresponding esters in which the radical R = C02R2, CH2C02R2 or OCHjCOsR2 (in particular if R2 is a methyl or ethyl radical) Treatment can be obtained with an aqueous concentrated ammonia solution.

These compounds can also be reacted further by conventional methods to prepare compounds of the formula (I) in which the radical R has the following meaning: CONHR3, CH2CONHR3 or OCH2CONHR3, where R3 is an alkanoyl, alkylsulfonyl, benzoyl or benzenesulfonyl radical. Thus, the carbamoyl derivatives, where R is CONHR3, CH2-CONHR3 or OCOCHNHR3, where R3 is a CrC4 alkanoyl residue, can be prepared by an acylation reaction, e.g. using the imidazolide derivative obtained from a C1-C4 alkane carboxylic acid by reaction with N, N'-carbonyld'iimidazole. A similar reaction can be used to prepare compounds in which R3 is benzoyl, e.g. using benzoic acid and N, N'-carbonyldiimidazole. The compounds in which R3 is a cyano radical or an alkylsulfonyl radical or a benzenesulfonyl radical can be prepared in a similar manner by reacting the corresponding acid, where R is C02H, CH2C02H or 0CH2C02H, with N ^ '- carbonyldiimide'azole and adding cyanamide or the required alkylsulfonamides or benzenesulfonamides are prepared, in which case the product is obtained in its tautomeric form, ie as a carboximidic acid derivative. Compounds in which R1 is a sulfonamido radical can be obtained from the unsubstituted compound of formula (I), wherein R is a hydrogen atom, by a chlorosulfonylation reaction, e.g. by reaction with chlorosulfonic acid and phosphorus pentachloride, and 1 subsequent treatment with an aqueous, concentrated ammonia solution. Compounds in which R is or contains a tetrazolyl radical can be prepared from the corresponding cyano derivative by reaction with sodium azide and ammonium chloride.

All of the aforementioned conversion reactions are completely conventional, and the conditions for carrying them out are known to those skilled in the art as well as other ways and modifications thereof.

The starting compounds of formula (II) are generally known compounds. They can be obtained from a suitably substituted phenol by reaction with sodium hydride and an arylsulfonyloxyethyl or propyl halogenide for the preparation of the compounds of the formula (II), in which n = 2 and 3, respectively.

It has been found that compounds of the formula (I) selectively inhibit the action of the thromboxane synthetase enzyme without significantly influencing the action of the prostacyclin synthetase or cyclo-oxygenase enzymes. The compounds according to the invention are therefore valuable in the treatment of a large number of clinical conditions which are characterized by a non-balance of prostacyclin / thromboxane-A2. For the reasons listed below, such conditions may include thrombosis, ischemic heart disease, strokes, transient ischemic attacks, migraines and vascular complications from diabetes.

Research has shown that the main product of arachidonic acid metabolism in most tissues is one of two non-stable substances, namely throm-boxan-A2 (TxA2) or prostacyclin (PGI2), see Proc. Nat. Acad. Sci., USA, 72: 2994 (1975); Nature, 263 (1976), 663; Prostaglandins, 12 (1976), 897. In most cases, the prostaglandins PGE ^ PGF2tt and 'PGD2 are small amounts of by-products present in this bio-synthetic route. The discovery of thromboxane-A2 and prostacyclin has significantly increased understanding of vascular homeostasis, for example prostacy-io clin is a powerful vasodilator and inhibitor for platelet aggregation, and in the latter regard it is the most potent endogenous substance , which has been discovered so far.

The prostacyclin synthetase enzyme is located in the endothelium 15 layer of the vascular system and is fed by endoperoxides which are released by the platelets which come into contact with the vascular wall. The prostacyclin formed in this way is important for the prevention of the deposition of platelets on the vascular walls, see Prostaglandins, 12 (1976), 685; Science 17

(1976); and Nature 273 (1978), 765.

Thromboxan-As is synthesized by the thromboxane synthetase enzyme, which is located, for example, in the platelets. ThromboxanrA2 is a powerful vaso-25 constrictor and a strong pro-aggregator. As such, its effects are directly opposite to those of prostacyclin. Therefore, if for any reason prostacyclin formation is inhibited by the vascular system, the endoperoxides formed by the platelets that come into contact with the vascular wall are converted to thromboxane, but they are not effectively converted to prostacyclin, see Lan -cet (1977), 18 and Prostaglandins, 13 (1978), 3. A change in the equilibrium of prostacyclin / thromboxane 35 in favor of the latter substance could therefore result in platelet aggregation, vasospasm, see Lancet

(1977), 479; Science (1976), 1135; and Amer. J. Cardio-logy, 41 (1978), 787 and an increased susceptibility to atherothrombosis, see Lancet, (i) (1977), 1216. Wei-

40 Furthermore, it is known that prostacyclin formation is suppressed and thromboxane A2 formation is promoted in the experimental atheroskle dose, see Prostaglandins, 14 (1977) 1025 and 1035. Therefore, thromboxane A2 was used as a causative agent in various angins, viewed myo-45 cardiac infarction, sudden cardiac death and strokes, see thromb. Haemostasis, 38 (1977), 132. Studies in rabbits have shown that typical changes in the ECG for these conditions occurred when freshly produced thromboxane-A2 was injected directly into the animal heart, see Biochem. Aspects of Prostaglandins and Thromboxanes, edited by N. Kharasch and J. Fried, Academic Press (1977), page 189. This mode of operation is considered to be an excellent animal model for heart attacks for cardiac patients and has been used to demonstrate 55 that the administration of a compound, which is believed to antagonize the effects of thromboxan-A2, which protects rabbits from the adverse effects of thromboxan-A2 injection.

Another area in which an imbalance 60 of PGI2 / TxA2 is considered a contributing factor is that of migraines. Migraine headache is associated with changes in the intra- and extra-cerebral blood flow, in particular with a reduction in the cerebral blood flow before the occurrence of the headache and subsequent dilation in both vascular areas during the headache phase.

Before the development of the headache, blood levels of 5-hydroxytryptamine are increased, and this puts that down

Occurrence of in vivo aggregation and the release of the amine from the storage sites in the platelets close. It is known that platelets in migraine sufferers have a greater tendency to aggregate or clot than those in normal individuals, see J. clin. Pathol. 24: 250 (1971); J. Headache, 17 (1977), 101.

Furthermore, it has recently been postulated that not only the abnormality of platelet function is a main factor in the pathogenesis of migraine attacks, but actually the main cause thereof, see Lancet (i) (1978), 501. Therefore, an active ingredient which selectively reduces platelet function Inhibition of thromboxane A2 formation modified to be of considerable advantage in migraine therapy.

Platelet behavior abnormalities have been reported for patients with diabetes mellitus, see Metabolism, 28 (1979), 394; and Lancet (i) (1978), 235. Diabetes patients are known to be particularly susceptible to microvascular complications, atherosclerosis and thrombosis, and platelet hyperreactivity was considered to be the cause of such angiopathy. Platelets from diabetes patients form increased amounts of TxB2 and mellondialdehyde, see symposium “Diabetes and Thrombosis-Impücations for Therapy”, Leeds, Great Britain (April 1979). Furthermore, it was shown that vascular prostacyclin formation is inhibited in rats with experimentally produced diabetes and that TxA ^ synthesis from the platelets is increased, see IV. International Prostaglandin Conference, Washington, D.C. (May 1979). Therefore, the imbalance between prostacyclin and TxA2 is considered to be responsible for the microvascular complications in diabetes. An inhibitor of TxA2 synthetase could therefore be used clinically to prevent these vascular complications.

Aspirin and most other non-steroidal, anti-inflammatory agents inhibit the cyclo-oxygenase enzyme. The effect of this enzyme is to reduce the formation of PGG2 / H2 endoperoxides and thus to reduce both the levels of prostacyclin and thromboxane ^. Aspirin and aspirin-like agents have been clinically tested for the prevention of stroke and heart attack, see New England, J. Med., 299 (1978), 53; B.M.J. (1978), 1188; and 'Stroke, 8 (1977), 301.

Although some encouraging results have been obtained with these drugs, a compound that specifically inhibits thromboxane imaging and leaves prostacyclin biosynthesis unaffected would be more valuable in such kinetic conditions, see Lancet (ii), (1978),

780.

The effect of the compounds of the formula (I) according to the invention on the thromboxane synthetase enzyme and the prostacyclin synthetase and cyclo-oxygenase enzymes was determined according to the following in vitro enzyme determinations:

5 644597

generated isometric tension in the absence of the test connection and following a preincubation of the enzyme with the test compound were measured for 5 minutes.

5

2. Prostacyclin (PG1 J synthetase

Microsomes from a porcine aorta [Nature, 263 (1976), 663] were incubated for 30 seconds at 22 ° C. with PGH2, which had been prepared in accordance with the statements made under 1 above, and aliquots were prepared as described under 1 biologically examined. PGI2 formation was measured indirectly by measuring the decrease in PGH2-induced tension; PGI2 itself does not result in aortic contraction. This decrease can be completely prevented by preincubating the enzyme with the selective PGI2 synthetase inhibitor, 15-hydroperoxyarachidonic acid [Prostaglandins, 12 (1976), 715]. The test compound is then preincubated with the enzyme for 5 minutes and its ability to prevent the train from decreasing is measured.

3. Thromboxan-A2 (TxA.J synthetase

Human platelet microsomes pretreated with indomethacin [Science, 193 {1976), 163] were incubated for 2 minutes at 0 ° C. with PGH2, which had been generated as described under 1., and parts of the reaction mixture were passed over two spirals flow from rabbit aorta separated by a delay spiral (2 minutes). This delay spiral is necessary to enable the more unstable thromboxane-A2 to decay selectively, see Proc. Nat. Acad. Sei., 72 (1975), 2994, which enables separate measurement of the increased isometric pull as a result of the TxA2 formed and the remaining PGH2. 35 The test compound is preincubated1 with the enzyme for 5 minutes and its ability to inhibit the thromboxane synthetase enzyme is measured as a reduction in the TxA2 component of the isometric pull.

The 40 compounds according to the invention investigated in this way showed that they are able to selectively inhibit the thromboxane synthetase enzyme. The results of these tests are summarized in Table I below, indicating the molar concentration of each compound which caused a 50% change in the effect of the relevant enzyme on the isometric pull, i.e. caused a 50% inhibition of the action of this enzyme. Furthermore, the ratios of the molar concentrations which cause a 50% inhibition of the effects of the prostacyclin synthetase and 'thromboxane 50 synthetase enzymes are given, this being an indication of the ability of the compounds to selectively inhibit the action of the latter Enzyme relative to the former enzyme.

1 cyclo-oxygenase

Cat's seminal vesicle microsomes [Biochemistry, 70 (1971), 23721 were incubated with arachidonic acid (100 n, M: 1 min: 22 ° C) to form PGH2, and equal 60 aliquots of the reaction mixture were placed in a flow of cancer bicarbonate solution at 37 ° C, which is a mixture of antagonists [Nature, 218, (1978), 1135] and indomethacin [Brit. J. Pharmacol., 45 (1972), 451], which flows over a spiral-cut rabbit 65 chena orta strip [Nature, 223 (1969), 29]. The ability of a compound to inhibit the enzyme was measured by measuring the increases in PGH2

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6

TABLE I

Example molar concentration for 50% inhibition of: ratio of (3)

(1) thromboxane (2) cyclooxygenase (3) prostacyclin to (1)

synthetase synthetase

1

2.2

X

IO "8

> 10 ~ 4

> 10 "4

> 4,500

2nd

1.0

X

10-®

3rd

1.0

X

IO "6

4th

4.0

X

10 "8

> 10 "4

> 2,500

7

4.6

X

10-0

1 X 10 "4

2,200

8th

3.4

X

10 "8

> 10-4

> 2,900

16

3.8

X

10 "10

> 10-4

> 10 "4

> 260,000

17th

3.4

X

10-5

18th

4.2

X

10 "9

19th

5.8

X

10 "7

21st

1.2

X

10 "8

22

4.9

X

10-®

23

1.6

X

10 "8

24th

5.0

X

10 "9

> 10 "4

> 10 "4

> 20,000

25th

5.6

X

10-9

1

O

A

> 10 "4

> 18,000

26

1.0

X

10-®

39

6.6

X

10-6

The results summarized in Table I show that all of the compounds tested caused 50% inhibition of thromboxane synthetase enzyme at a molar concentration of 1.0 X 10-5 or less, and that several compounds caused 50% inhibition Caused concentrations of 10-8 or less.

Of the compounds investigated to inhibit the cyclo-oxygenase enzyme, no compound caused 50% inhibition at molar concentrations of 10 ~ 4 or less, and their ability to inhibit this enzyme was at least 4500 times less and in several cases more than that was 100 times less than their ability to inhibit thromboxane synthetase enzyme.

Of the compounds examined to inhibit prostacyclin synthetase enzyme, no compound caused 50% inhibition at molar concentrations which was more than 2000 times greater than the concentration at which it inhibited thromboxane synthetase by 50% -enzyme caused, ie all compounds were at least d'as 2000 times more effective as inhibitors of thromboxane synthetase than inhibitors of pro-stacycline synthetase.

It is believed that all compounds according to the invention, when tested in this manner, will show results within the range of the compounds already tested.

An in vitro study to measure inhibition of platelet aggregation in humans has also been described, and this may predict clinical antithrombotic activity, see Lancet (ii) (1974), 1223; and J. Exp. Med., 126 (1967), 171.

Both clinically active agents aspirin and sulfinpyra-zon show inhibitory activity in vitro against a variety of lump-forming agents in this test.

A number of in vivo tests in animals have also been described for the classification of potential antithrombotic agents. The intravenous injection of arachidonic acid causes death in rabbits by causing clumping of the platelets and embolism in the lungs. The two clinically active agents 45 Aspirin [Agents and Action, 1 (1977), 481] and Sulfinpyrazone [Pharmacology, 14 (1976), 522] protect the rabbit from the lethal effect of the injection. Sul-finpyrazone has also been shown to prevent platelet aggregation in an out-of-body loop of the abdomen aorta in rats in vivo, see Thromb. Diathes, Haem., 30 (1973), 138. The inventive compound of Example 16 was tested according to the methods given above, and was found to prevent aggregation of blood 55 platelets in humans, for protection of rabbits before the lethal effect of arachidonic acid injection and 'to prevent platelet aggregation in the rat aorta.

60 The compounds according to the invention can be administered orally in the form of tablets or capsules which contain a unit dose of the compound together with such diluents as corn starch, calcium carbonate, dicaicium phosphate, aginic acid, lactose, magnesium stearate, Primogel (trademark) 65 or talc . The tablets are made in a conventional manner by granulation of the ingredients and presses, the capsules by filling into hard gelatin capsules of the appropriate size, so that the

7

644597

se contain the ingredients, optionally after granulation.

The compounds according to the invention can be administered parenterally, for example by intramuscular, intravenous or subcutaneous injection. For parenteral administration, they are best used in the form of a sterile, aqueous solution, which can contain other, dissolved substances such as tonic agents and 1 agent for adjusting the pH. The compounds can be added to distilled water and the pH adjusted to 3 to 6 using an acid such as citric acid, lactic acid or hydrochloric acid. Sufficiently dissolved substances such as dextrose or saline can be added to make the solution isotonic. The solution obtained can then be sterilized and filled into sterile glass ampoules of a suitable size so that they contain the desired solution volume. The compounds according to the invention can also be administered into a vein by infusion of a parenteral formulation as described above.

For oral administration in humans, it is assumed that the daily dose value of a compound according to the invention is in the range from 0.1 to 20 mg / kg per day for a typical adult patient of 70 kg. For parenteral administration, it is assumed that the daily dose value of a compound of formula (I) is from 0.01 to 0.5 mg / kg per day for a typical adult patient. Therefore, tablets or capsules can usually contain 5 to 150 mg of active compound for oral administration up to three times a day. The dosage units for parenteral administration can contain from 0.5 to 35 mg of active compound. A typical ampoule could therefore be a 10 ml ampoule containing 5 mg of the active compound in 6 to 10 ml of solution.

Of course, the doctor will in any case determine the actual dosage which is most suitable for the individual patient, this with the same

Age, weight and patient response may vary. The aforementioned dosages are examples for an average patient, although there can of course be individual cases in which higher or lower dosage ranges are more advantageous.

The preparation of the compounds according to the invention is shown using the following examples:

example 1

10 l- [2- (4-carbamyophenoxy) ethyl] imidazole

14.4 g of sodium hydride1 as a 50% suspension in mineral oil were carefully added to a stirred and cooled solution of 20.4 g of imidazole in 100 ml of dry N, N-Di-15 methylformamide. After the initially violent reaction subsided, the mixture was heated at 100 ° C for 10 minutes and then stirred at room temperature for an additional hour. A solution of 60.0 g of 4- (2-chloro-ethoxy) benzamide in the minimum volume of N, N-Dime-20 thylformamide was added and the mixture was heated at 100 ° C for 5.5 hours. The solvent was evaporated and the residue was poured into water. The mixture was extracted several times with chloroform and the combined chloroform extracts were dried over 25 MgSO4 and evaporated to give a mixture of oil and solid. The mixture was triturated with ether and the solid was collected and crystallized from a mixture of methanol and ethyl acetate, giving 35.2 g of l- [2- (4-'carbamoylphenoxy) ethyl] -3o -imdazole with F. 148- 149 ° C were obtained.

Analysis on C12H13N302:

found: C 62.25 H 5.61 N 18.54% calculated: C 62.32 H 5.67 N 18.17%

35 In a similar manner, further compounds were prepared using the correspondingly substituted (2-chloro) -ethoxy-benzene compound instead of 4- (2-chloro-ethoxy) -benz-amide. These are in the. following tables II and III.

TABLE II

example

R

F. (° C)

Crystallization solvent

Analysis in% (theoretical values in brackets) C H N

2nd

2-CONH2

147-148 °

Ethylmethyl

61.94

5.65

17.87

ketone

(62.32

5.67

18.17)

3rd

4-CH? CONH2

147-149 °

Ethylmethyl

63.64

6.09

16.94

ketone

(63.66

6.16

17.13)

4th

2-C02C2H5

89-90.5 °

Isopropanol

57.73

5.34

7.59

(57.44

5.36

7.44) 2

5

3-CN

126-128 °

Isopropanol /

58.55

4.77

16.73

Ethyl acetate

(57.72

4.85

16.83) 1

6

2-CH2C02C2H5

129.5-130.5 °

Isopropanol /

58.25

6.21

9.09

Ethyl acetate

(57.97

6.16

9.02) 1

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8th

TABLE II (continued)

Example R F. (° C) crystallization analysis in%

solvents (theoretical values in brackets)

C H N

7

3-CH2C02C2Hs

'130-131 °

Methanol /

58.24

5.60

7.44

Ethyl acetate

(58.45

5.68

7.18)

8th

4-CH2C02C2H5

101.5-103 °

Ethyl acetate

58.54

5.68

7.23

(58.45

5.68

7.18)

9

4-0CH2C02C2H5

97-98 °

Ethyl acetate

55.65

5.64

6.71

(56.15

5.46

6.89)

10th

4-N02

56-57 °

Ethyl acetate /

56.25

4.75

17.88

Petroleum ether

(56.65

4.76

18.02)

11

4-nhcoch3

168-170 °

Ethyl acetate

63.43

6.13

16.70

(63.66

6.16

17.13)

12 4-CN

1 hydrochloride salt

2 maleate salts

3 fumarate salt

4 purified using chromatography over Si02. Elution with ethyl acetate gave l- (4-N-nitrophenyl) imidazole as a by-product. The product was eluted with ethyl acetate / MeOH (9: 1).

Example R R1 F. (° C) Crystallization Analysis in%

solvent theoretical value in brackets)

C H N

13 4-CONH2 2-och3 154-156 ° methanol / 58.58 5.61 15.46

Ethyl acetate (58.75 5.88 15.81)

14 4-C02C2H5 2-C1 90 ° ethyl acetate / not further characterized

Petroleum ether

15 5-C02C2H5 2-ch3

Example 16 l- [2- (4-Carboxyphenoxy) Ethyl] imidazole

A solution of 4.5 g of l- [2- (4-carbamoylphenoxy) ~ ethyl] imidazole in 20 ml of 5N hydrochloric acid was heated at 100 ° C. for 2 hours and then cooled. The solid obtained was filtered off, 4.55 g of l- [2- (4-carboxyphenoxy) ethyl] imidazole hydrochloride having a melting point of 233-235 ° C., after crystallization from acetic acid increased to a temperature of F. 241 ° C were obtained.

Analysis on C12H12N203. HCl:

found: C 53.93 H 4.99 N 10.91% calculated: C 53.64 H 4.88 N 10.43%

55 Example 17

1- [2- (2-carboxyphenoxy) ethyl] imidazole hydrochloride

A solution of 5.1 g of l- [2- (2-ethoxycarbonyl-phenoxy) - ethyl] -imidazole, prepared by treating the maleate 60 salt with NaOH and then extracting with ethyl acetate, in 30 ml of 5N hydrochloric acid was placed on a Steam bath heated for 8 hours and then evaporated. The residue was recrystallized from isopropanol to give 3.08 g of l- [2- (2 - carboxyphenoxy) ethyl] imidazole hydrochloride with mp 138-65 to 139.5 ° C.

Analysis on C12H12N203. HCl:

found: C 53.61 H 4.88 N 10.46% calculated: C 53.64 H 4.88 N 10.43%

9

644 597

Example 18

4- [2- (l-Imidazolyl) cithoxy] phenoxyacetic acid hydrochloride

A solution of 1.6 g of ethyl 4- [2- (l-imidazolyl) ethoxy] phenoxyacetate, prepared by treating the fumarate salt with NaOH and then extracting it with ethyl acetate, in 10 ml of 5N hydrochloric acid was on a steam bath Heated for 18 hours and then evaporated. The residue was recrystallized from acetonitrile to give 0.72 g of 4- [2- (l - imidazolyI) ethoxy] phenoxyacetic acid hydrochloride with mp 162-164 ° C.

Analysis on C13H14N204. HCl:

found: C 52.10 H 4.96 N 9.65% calculated: C 52.27 H 5.06 N 9.38%

Example 19

2- [2- (l-imidazolyl) ethoxy] phenylacetic acid hydrochloride

A solution of 3.5 g of ethyl 2- [2- (l-imidazolyl) ethyl] phenylacetate hydrochloride in 20 ml of 5N hydrochloric acid was heated on a steam bath for 6 hours and then evaporated. The residue was recrystallized from isopropanol to give 2- [2- (l-imidazolyl) ethoxy] phenylacetic acid hydrochloride with mp 146-147 ° C.

Analysis on C15Hi4N203. HCl:

found: C 54.69 'H 5.25 N 9.80% calculated: C 55.22 H 5.35 N 9.91%

Example 20

1- [2- (4-carboxy-2-chlorophenoxy) ethyl] imidazole

A mixture of 115 mg of l- [2- (4-ethoxycarbonyl-2-chlorophenoxy) ethyl] imidazole and 50 mg of potassium hydroxide in 6.25 ml of water were heated on a steam bath for 18 hours. The solution obtained was just acidified with acetic acid and evaporated to a small volume. The solid obtained was filtered off, washed with water and recrystallized from water, 65 mg of l- [2- (4-carboxy-2-chlorophenoxy) ethyl] imidazole having a melting point of 204 ° C. being obtained.

Analysis for C] 2HnClN203:

found: C 53.44 H 4.15 N 10.52% calculated: C 54.04 H 4.16 N 10.51%

Example 21

1- [2- (3-carboxyphenoxy) ethyl] imidazole hydrochloride

A mixture of 2.0 g of l- [2- (3-cyanophenoxy) ethyl!] Imidazole hydrochloride and 5N sodium hydroxide was heated on a steam bath for 6 hours to form a clear solution. The solution was acidified with dilute hydrochloric acid and evaporated to dryness. The residue was extracted with hot acetic acid and the solution was filtered and evaporated. The residue was recrystallized from acetic acid to give l- [2- (3-carboxy-phenoxy) -ethyl-imidazole hydrochloride with mp 232-233 ° C.

Analysis on Ci2Hi2N203. HCl:

found: C 53.13 H 4.69 N 10.68% calculated: C 53.64 H 4.88 N 10.43%

Example 22 l- [2- (4-Tetrazol-5-ylphenoxy) ethyl] imidazole

A mixture of 2.1 g of l- [2- (4-cyanophenoxy) ethyl] imidazole, 3.25 g of sodium azide and 2.67 g of ammonium chloride in 25 ml of dry N, N-dimethylformamide was placed on a steam bath for 22 Heated for hours. The solution was evaporated and the residue was washed with chloroform. The chloroform extract was filtered and evaporated and the residue was crystallized from aqueous ethanol to give 0.81 g of l- [2- (4-tetrazol-5-ylphenoxy) ethyl] imidazole with mp 196-197 ° C were obtained.

Analysis on Ci2H12NbO:

found: C 56.30 H 4.76 N 33.20% calculated: C 56.24 H 4.72 N 32.80%

Example 23

4- [2- (1-1 midazolyl) ethoxy] phenoxyacetamide

A mixture of 1.0 g of the free base of ethyl 4- [2 - (l-imidazolyl) ethoxy] phenoxyacetate, 10 ml of ethanol and 20 ml of concentrated ammonia solution was left at room temperature for 20 hours to form a clear solution. The solution was evaporated and the residue was recrystallized twice from 2-butanone to give 0.38 g of 4- [2- (l-imidazolyl) ethoxy] phenoxyacetamide, mp 123-124 ° C.

Analysis on C13H] 5N303:

found: C 59.70 H 5.77 N 16.26% calculated: C 59.76 H 5.79 N 16.08%

Example 24

1- [2- (4-N-Methylcarbamoylphenoxy) ethyl] imidazole

1.0 ml of thionyl chloride was added dropwise to a stirred mixture of 1.0 g of l- [2- (4-carboxyphenoxy) ethyl] imidazole hydrochloride and 5 ml of dry N, N-dimethylformamide at room temperature. The clear solution obtained was stirred for 5 hours. The solution was then added dropwise to a stirred solution of 20 ml of 40% aqueous methylamine and the resulting mixture was evaporated to dryness. The residue was taken up in water and the solution was made basic by adding sodium bicarbonate. The mixture was evaporated and the residue was extracted twice with hot ethyl acetate. The extract was filtered and evaporated to give an oil which solidified on standing. The solid was recrystallized from ethyl acetate to give 0.68 g of l- [2- (4-N-methylcarbamoylphenoxy) ethyl] imide-azole with mp 132-133 ° C.

Analysis on C13H15N302:

found: C 63.41 H 6.14 N 17.24% calculated: C 63.66 H 6.16 N 17.13%

Example 25

1- [2- (4-N, N-Dimethylcarbamoylphenoxy) ethyl] imidcizole

The successive treatment of 1.0 g of l- [2- (4-carboxyphenoxy) ethyl] imidazole hydrochloride with 1.0 ml of thionyl chloride and 20 ml of 50% strength aqueous dimethylamine as described in Example 24 gave l- [2 - (4-N, N-DimethylcarbamoyIphenoxy) ethyl] imidazole, isolated in the form of the fumarate salt with mp 113-115 ° C (from ethyl acetate).

Analysis on C14H17N302. C4H404:

found: C 57.11 H 5.52 N 11.05% calculated: C 57.59 H 5.64 N 11.19%

Example 26

1- [4- (2-Imidazol-l-yl) -'thoxybenzoyl] marpholine

The successive treatment of 1.4 g of l- [2- (4-carboxyphenoxy) ethyI] imidazole with 1.4 g of thionyl chloride and 10 ml of 'morpholine as described in Example

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644597

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25 gave N- [4- (2-imidazol-l-yl) -ethoxybenzoyI] morpholine with mp 109-111 ° C (from ethyl acetate).

Analysis on C16H19N303:

found: C 63.80 H 6.40 N 13.87% calculated: C 63.77 H 6.36 N 13.94%

Example 27 l- [2- (4-Sulfamoylphenoxy) ethyl] imidazole

2.08 g of phosphorus pentachloride was carefully added to 2.91 g of chlorosulfonic acid, and the resulting solution was cooled to 0 ° C. 1.88 g of l- (2-phenoxyethyl) imidazole were added in portions, the foaming reaction being allowed to subside after each addition. The mixture was heated on a steam bath for 10 minutes, cooled, and poured onto a mixture of crushed ice and excess concentrated ammonia solution. The rubber-like solid obtained was filtered off, washed with water, suctioned off as dry as possible on a filter pump and chromatographed on silica gel. Elution with a mixture of chloroform and ethanol (4: 1) gave a resinous substance which crystallized when triturated with a few ml of ethanol. The solid was crystallized from ethanol to give 0.5 g of l- [2- (4-sulfamoylphenoxy) ethyl] imidazole, mp 147.5 to 148.5 ° C.

Analysis on CnH13N303S:

found: C 49.57 H 4.93 N 15.36% calculated: C 49.42 H 4.90 N 15.72%

Example 28 l- [2- (4-A minophenoxy) ethyl] imidazole

6.0 g of iron powder were added in portions to a warm solution of 3.7 g of l- [2- (4-nitrophenoxy) ethyl] imidazole in 60 ml of 5N hydrochloric acid. After 20 minutes the solution was cooled, basified with dilute sodium hydroxide solution and the mixture was shaken with chloroform and filtered. The chloroform layer of the filtrate was separated, dried over Na2S04 and evaporated to give a solid. This was recrystallized from ethyl acetate / petroleum ether, giving 2.25 g of l- [2- (4-aminophenoxy) ethyl] imidazole with a melting point of 91-92 ° C.

Analysis on CnH13N30:

found: C 64.35 H 6.40 N 20.61% calculated: C 65.01 H 6.45 N 20.68%

Example 29

l-l 2- (4-methoxycarbonylaminophenoxy) ethyl} imidazole

0.5 g of methyl chloroformate was added to a stirred solution of 1.0 g of l- [2- (4-aminophenoxy) ethyl] imidazole in 50 ml of chloroform, and the mixture was stirred at room temperature for 2 hours and then evaporated. The residue was dissolved in water and made basic with the addition of sodium bicarbonate. The precipitate obtained was filtered off, washed with water and crystallized from methanol / water, 1.13 g of 1 - [2- (4-methoxycarbonylaminophenoxy) ethyI] imidazole having a melting point of 152-153 ° C. being obtained.

Analysis on C13H] 5N303:

found: C 59.77 H 5.81 N 15.92% calculated: C 59.76 H 5.79 N 16.08%

Example 30 l- [2- (4-ureidophenoxy) ethyl] imidazole

0.6 g of l- [2- (4-aminophenoxy) ethyl] imidazole was dissolved in 3.0 ml of 1N hydrochloric acid and a solution of 0.3 g of potassium cyanate in 1 ml of water was added. The mixture was allowed to stand at room temperature for 15 minutes and the solid obtained was filtered off, washed with water and recrystallized from water, giving 0.6 l of [2- (4-ureidophenoxy) ethyl] imidazole with mp 199-201 ° C were obtained.

Analysis on C12H14N402:

found: C 58.20 H 5.70 N 23.06% calculated: C 58.52 H 5.73 N 22.75%

Example 31

1- [2- (4-aminomethylphenoxy) ethyl] imidazole dihydrochloride

A solution of 8.6 g of l- [2- (4-cyanophenoxy) ethyl] imidazole in 70 ml of dry tetrahydrofuran was added dropwise to a stirred suspension of 3.8 g of lithium aluminum hydride in 150 ml of dry tetrahydrofuran under reflux conditions. The mixture was stirred under reflux conditions for 3 hours and then at room temperature for 18 hours. 4 ml of water and then 16 ml of 1.25N sodium hydroxide solution were carefully added. The mixture was filtered and the filtrate was evaporated to give an oil which was chromatographed on silica gel. Elution of the acid with chloroform / methanol (20: 1) gave 5.7 g of the pure product in the form of an oil.

Part of the oil was dissolved in chloroform and treated with an excess of ethereal hydrochloric acid. The solid was filtered off and crystallized from ethanol, giving '1- [2- (4-aminomethylphenoxy) ethyl] imidazole dihydrochloride with mp 216-217 ° C.

Analysis on C12H] 5N30. 2HC1: c found: C 49.34 H 5.94 N 14.60% calculated: C 49.66 H 5.91 N 14.48%

Example 32

1- [2- (4-acetylaminomethylphenoxy) ethyl] imidazole

1.1 g of l- [2- (4-aminomethylphenoxy) ethyl] imidazole was heated on a steam bath for 2 hours in a mixture of 10 ml of acetic acid and 1 ml of acetic anhydride. The solution was then evaporated and the residue was dissolved in a small volume of water. The solution was made basic with sodium bicarbonate and the solid obtained was filtered off, washed with water and recrystallized from water, giving 0.70 g of l-f2- (4-acetylaminomethylphenoxy) ethyl] imidazole with mp 115 to 116 ° C were obtained.

Analysis on C14Hi7N302. HaO:

found: C 60.45 H 6.72 N 15.35% calculated: C 60.63 H 6.9 î N 15.15%

Example 33

1- [2- (4-ureidomethylphenoxy) ethyl] imidazole

1.1 g of l- [2- (4-aminomethylphenoxy) ethyl] imidazole was dissolved in 7 ml of 1N hydrochloric acid and a solution of 0.5 g of potassium cyanate in 1 ml of water was added. The solution was left at room temperature for 30 minutes and then briefly heated to 100 ° C and cooled. The solid obtained was filtered off and recrystallized twice from water, giving 0.33 g of l- [4- (2-ureidomethylphenoxy) ethyl] imidazole with mp 198-199 ° C.

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644 597

Analysis on Ci3H16N402:

found: C 59.24 H 6.13 N 21.96% calculated: C 59.98 H 6.20 N 21.53%

Example 34

1- [2- (A cetylcarbamoylphenoxy) ethyl] imidazole

4.9 g of N, N'-carbonyldiimidazole was dissolved in 10 ml of dry N, N-dimethylformamide and 1.8 g of acetic acid was added. The solution was stirred for 5 minutes and then 4.6 g of l- [2- (4-carbamoylphenoxy) ethyl] imidazole was added. The solution was heated under reflux for 3 hours and then evaporated 1. The residue was treated with aqueous sodium bicarbonate solution and the mixture was extracted several times with ethyl acetate. The combined ethyl acetate extracts were washed with water, dried over Na2SO4 and evaporated to give an oil which was chromatographed on silica gel. Elution with chloroform resulted in some contamination. A further elution with chloroform / methanol (50: 1) gave a solid which was crystallized from 2-butanone, 0.9 g of l- [2- (4-acetylcarbamoylphenoxy) ethyl] imidazole with F. 164 -165 ° C were obtained.

Analysis on C14HigN303:

found: C 61.28 H 5.54 N 15.51% calculated: C 61.53 H 5.53 N 15.38%

Example 35

1- [2- (4-Benzoylcarbamoylphenoxy) cithyl] imidazole

Treatment of benzoic acid with N, N'-carbonyidimidazole and 1- [2- (4-carbamoylpheoxy) ethyI] imidazole in dry N, N-dimethylformamide as described in Example 34 gave 1- [2- (4th -Benzoylcarbamoyl-phenoxy) -äthyll-imidazol mit.F. 152-154 ° C (from methanol / ethyl acetate).

Analysis on C19H17N303:

found: C 67.66 H 5.16 N 12.59%

calculated: C 68.05 H 5.11 N 12.53%

Example 36

N-methylsulfanyl-4- [2- (l-imidazolyl) ethoxy] benzene carboximidic acid

A mixture of 3.3 g of l- [2- (4-carboxyphenoxy) ethyl] imidazole, prepared from the hydrochloride salt by dissolving in water, adjusting the solution to just alkaline conditions with dilute sodium hydroxide solution and then precipitating by adding acetic acid, and 3.0 g of N, N'-carbonyldiimidazole were heated on a steam bath for 2 hours, then 3.2 g of methanesulfonamide were added. The mixture was heated to 150 ° C for 2.5 hours and then cooled slightly and taken up in a minimal volume of ethanol. The solid which precipitated on cooling was cooled and washed with water, giving N-methylsulfonyl-4- [2- (1-imidazolyI) ethoxy] benzene carboxamic acid with mp 198 to 199 ° C.

Analysis on C13Hi5N304S:

found: C 50.37 H 4.84 N 13.67%

calculated: C 50.47 H 4.89 N 13.59%

Example 37

N-benzenesulfonyl-4- [2- (l-imidazolyl) cithoxyl-benzenecarb-

oximic acid

Treatment of 1- [2- (4-carboxyphenoxy) ethyl imidazole with N, N'-carbonyldiimidazole and then with benzenesulfonamide as described in Example 36 gave N-benzenesulfonyl-4- [2- (l-imidazolyl) -äth-oxy] -benzenecarboximidic acid with mp 250-252 ° C (from N, N-dimethylformamide / H20).

5 Analysis on C18H17N304S:

found: C 58.17 H 4.60 N 11.08% calculated: C 58.21 H 4.61 N 11.31%

Example 38

10 l- [3- (4-carboxyphenoxy) propyl] imidazole

A) 0.6 g of sodium hydride as a 50% suspension in mineral oil was carefully added to a stirred and cooled solution of 0.79 g of imidazole in 50 ml of dry N, N-dimethyl

15 thylformamide added. After the initially violent reaction subsided, the mixture was heated to 100 ° C for 10 minutes and then stirred at room temperature for an additional hour.

2.8 g of ethyl 4- (3-chloropropoxy) benzoate was added over 2 minutes, and the resulting mixture was heated on a steam bath for 6 hours and then cooled. 1 ml of water was added to decompose unreacted sodium hydride, the solution was evaporated and the residue was chromatographed on silica gel 25. Elution with chloroform gave a mineral oil-like product and low levels of contamination. Elution with chloroform / methanol (20: 1) gave the pure l- [3- (4-ethoxycarbonylphenoxy) propyl] iimazole in the form of an oil after evaporation of the solvent.

B) 0.75 g of the ester was added to a solution of 2.0 g of potassium hydroxide in 20 ml of water and the mixture was heated on a steam bath for 18 hours and then cooled. Acidification with acetic acid gave one

35 solids, this was filtered off and crystallized from water, 0.31 g of l- [3- (4-carboxyphenoxy) propyl] imide-azole having a melting point of 218 ° C. being obtained.

Analysis on Ci3H14N203:

found: C 63.11 H 5.77 N 11.18% 40 calculated: C 63.41 H 5.69 N 11.38%

Example 39

1- [2- (2-Carbamoylmethylphenoxy) cithyl / imidazole

A mixture of 3.5 g of l- [2- (2-carbäthoxymethylphen-45 oxy) ethyl] imidazole, 30 ml of concentrated aqueous ammonia and 10 ml of ethanol was heated at 120 ° C. in a pressure bottle for 18 hours. The mixture was cooled and evaporated and the oily residue was chromatographed on silica gel. Elution with Chlo-50 roform / methanol (4: 1) gave a solid which was recrystallized from isopropanol / ethyl acetate, giving 0.7 g of l- [2- (2-carbamoylmethylphenoxy) ethyl] imidazole with mp 116 -118 ° C were obtained.

Analysis on C13H15N302:

found: C 63.42 H 6.10 N 16.82% calculated: C 63.66 H 6.16 N 17.13%

Example 40

N-cyano-4- [2 - (] - imidazolyl) ethoxy] benzene carboximidic acid

60

Treatment of l- [2- (4-carboxyphenoxy) ethyl] imidazole with N, N'-carbon.yldiimidazole and then with cyanamide as described in Example 36 gave N-cyano-4- [2- (l -imidazolyl) -ethoxy] -benzenecarbox-65 imidic acid with F. 199-200 ° C (decomposition) (from water). Analysis on C13H12N402:

found: C 60.59 H 4.64 N 22.20% calculated: C 60.93 H 4.72 N 21.87%

644597

12

Example 41

1 g of l- [2- (4-carboxyphenoxy) ethyl] imidazole was added to 900 ml of distilled water, and the pH was adjusted to 5 with hydrochloric acid. 18 g of sodium chloride were added and the solution was made up to 2 liters. This solution was sterilized by filtration through a bacteria-retaining filter under aseptic conditions in 10 ml glass ampoules, so that it corresponded to the sterility test according to Appendix 121 of the British Pharmacopea 1973.

Example 42

Capsules were made from the following ingredients:

mg / capsule

1 - f 2- (4-carboxyphenoxy) ethyl] imidazole 20

Lactose 250

Corn starch 75

Magnesium stearate 5

350 mg

The ingredients were mixed thoroughly, granulated and then filled into hard gelatin capsules of the desired size.

Example 43

1 - [2- (4-Carboxyphenoxy) ethyl] imidazole hydrochloride

A solution of 17 g imidazole in 100 ml N-N-dimethylformamide was added to a slurry of 21 g sodium hydride in the form of a 57% dispersion in oil in 200 ml N-N-dimethylformamide. The mixture was heated on a steam bath for 15 minutes, cooled, diluted with 1.0 1 N, N-dimethylformamide and a solution of 50.1 g of 4- (2-chloroethoxy) benzoic acid in 200 ml of N was added , N-dimethylformamide added. The mixture was heated to 95 ° C for 2.5 hours and then cooled, and 100 ml of technical ethanol was added to destroy excess sodium hydride.

Then 100 ml of 6N hydrochloric acid was added and the solution was concentrated to a volume of 0.5 l by evaporation under reduced pressure. To the resulting slurry, 750 ml of acetone was added and the precipitate obtained was collected by filtration. The solid was suspended in a mixture of 670 ml of technical grade ethanol and 150 ml of water and heated under reflux. The solution was filtered while hot and evaporated to dryness under reduced pressure. The residue was recrystallized from 6N hydrochloric acid to obtain 20.8 g of a crude product. The recrystallization of 10 g from a mixture of technical grade ethanol and water gave 6.9 g (yield 21%) of 1- [2- (4-carboxyphenoxy) ethyl] imidazole hydrochloride in the form of i5 white crystals F. 239-241 ° C, which were identical to the product of Example 16.

Example 44

l ~ [2- (4-methoxycarbonylphenoxy) ethyl] imidazole

20th

The general procedure of Example 43 was repeated, but using methyl 4- (2-chloroethoxy) benzoate instead of 4- (2-chloroethoxy) benzoic acid.

The recrystallization of the product from a mixture 25 of acetone and hexane gave 20.9 g (yield = 54%) of 1- [2- (4-methoxycarbonylphenoxy) ethyl] imidazole in the form of white crystals with a melting point of 99-100 ° C. .

v ", ax. (KBr) 1729, 1715, 1604 cm "1.

30 Example 45

1 - [2- (4-Carboxyphenoxy) ethyl] imidazole hydrochloride

A solution of 12.3 g of l- [2- (4-methoxycarbonylphen-oxy) ethyl] imidazole in 50 ml of 6N hydrochloric acid was boiled under reflux for 1.5 hours. The reaction mixture was cooled and the crystalline precipitate was collected by filtration, washed with acetone and dried, giving 9.0 g (yield = 67%) of 1- [2- (4-'carboxyphenoxy) ethyl] imidtaol hydrochloride were obtained in the form of white crystals with 40 F. 238-241 ° C, which were identical to the product of Example 16.

v

Claims (11)

644597 2. Imidazole derivative according to claim 1, characterized in that n is 2 in the formula given. 2nd PATENT CLAIMS 1. Imidazold derivatives of the following general formula: M N (CH "> ~ - in l = J in which mean: R = N02, CN, S02NH2, Cj-Q-alkanoyl, C02R2, CH2CQ2- r2, och2co2r2, conhr3, ch2conhr3, och2- CONHR3, C0N (R4) 2, CH2CON (R4) 2, 0CH2C0N (R% NHR5, CH2NHRs, tetrazolyl, CH2-tetrazolyI and OCH2-tetrazolyl; R1 = H, CrC4 alkyl, CrC4 alkoxy or halogen; R2 = H or Q-Q alkyl; R3 = H, CrC4-alkyl, CrC4-alkanoyl, CrC4-alkylsulfonyl, CN, benzoyl or benzenesulfonyl, the phenyl ring in these benzoyl or benzenesulfonyl groups optionally having one or more CrC4-alkyl, CrC4-alkoxy or CF3- Radicals or halogen atoms is substituted; each R4 = CrC4-alkyl radical or two R4 radicals together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino radical; R5 = H, CrC4-alkanoyl, CrC4-alkoxycarbonyl, carbamoyl, Ci-C4-alkylcarbamoyl; and n = 2 or 3, as well as the pharmaceutically acceptable acid addition salts thereof. 3. imidazole derivative according to claim 2, characterized in that the radical R1 in the formula H is H. 4. imidazole derivative according to claim 3, characterized in that the radical R in the formula given is a carboxy radical, a carbamoyl radical or an N- (mono- or dimethyl) carbamoyl radical. 5 Compound of the formula I, in which R1 and n have the meaning given and R is CONH2, CN or CO2 ^, where R2 is CMD4-alkyl, hydrolyzed with an acid or a base. 5. imidazole derivative according to claim 4, characterized in that the carboxy radical, the carbamoyl radical or the N- (mono- or dimethyl) carbamoyl radical are present in the 4-position. 6. l- [2- (4-carboxyphenoxy) ethyl] imidazole as a compound according to claim 1. 7. Medicament, characterized by a content of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable acid addition salt thereof. 8. Medicament according to claim 7, characterized by the additional content of a pharmaceutically acceptable diluent and / or carrier. 9. A process for the preparation of imidazole derivatives of the formula I, in which R1 and n have the meaning given in claim 1 and R has the following meaning: N02, CN, Cj-C4-alkanoyl, COaR2, CH2C02R2, 0CH2C02R2, in which R2 is a Cj- C4-alkyl radical is CONH2, CH2CONH2 or OCH2-CONH2, characterized in that imidazole with an alkali metal hydride and then with a compound of the following formula Shark di) 10. A process for the preparation of imidazole derivatives of the formula I, in which R1 and n have the meaning given in claim 1 and R is C02H, characterized in that one obtained according to claim 9 11. The method according to claim 10 for the preparation of io l- [2- (4-carboxyphenoxy) ethyl] imidazole by hydrolysis of l- [2- (4-carbamoylphenoxy) ethyl] imidazole.